Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cigarette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal destruction. Here we show that the expression level of FCH and double SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that Fchsd1 knockout (Fchsd1-/-) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of Fchsd1-/- mice showed reduced inflammation and apoptosis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of Fchsd1-/- mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), a redox-sensitive transcription factor, following H2O2 stimulation. Conversely, Fchsd1 overexpression inhibited NRF2 nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of emphysema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.